A 24-year-old man who has sex with men (MSM) and was receiving pre-exposure prophylaxis (PrEP) presented in late January with five days of fever, headache, malaise, arthralgia, odynophagia, rash, diarrhea, nausea, and abdominal discomfort. At admission, he described the rash as pruritic and unaffected by over-the-counter anti-allergy medications. He reported multiple recent unprotected sexual encounters. He had strict PrEP adherence, up-to-date immunizations, and no recollection of sick contacts. His physical examination was significant for a fever of 39 °C, a diffuse reticulomacular rash, erythroderma on palms and soles, and diffuse lymphadenopathies (Figure).
Initial workup showed eosinophilia of 7.3% (reference range, 0 to 5%) without leukocytosis, hyperbilirubinemia (bilirubin level, 3.1 mg/dL; reference range, ≤1.2 mg/dL) with direct bilirubin predominance, elevated aminotransferase levels (aspartate aminotransferase level, 44 U/L [reference range, <40 U/L]; alanine aminotransferase level, 155 U/L [reference range, 7 to 45 U/L]), alkaline phosphatase level of 129 U/L (reference range, 35 to 137 U/L), and abnormal urinalysis with pyuria. Blood and urine cultures were negative. A chest X-ray and CT of the head were normal. An extensive infectious workup included testing for HIV, Epstein-Barr virus, cytomegalovirus, influenza A and B, respiratory syncytial virus (RSV), gonorrhea, chlamydia, coxsackievirus A, and hepatitis A, B, and C. Further workup was significant for positive coxsackievirus B4 (CVB4) with titers of 1:80. The patient received supportive treatment and was discharged home after fever resolution.
This patient was diagnosed with acute off-season, non-outbreak-related CVB4 infection. Coxsackieviruses are small RNA enteroviruses that are members of the Picornaviridae family. Most infections occur as part of outbreaks during the summer and fall seasons and are transmitted via the fecal-oral route. The incubation period is three to six days. Severity varies widely, from mild and flu-like or mononucleosis-like syndromes to fatal neurologic and/or cardiac presentations. Common presenting symptoms include fever, headache, gastrointestinal symptoms, and palm/sole-sparing maculopapular rash (as opposed to hand-foot-mouth disease, commonly cause by coxsackievirus A16, coxsackievirus A6, and enterovirus 71). According to the National Enterovirus Surveillance System, the most common clinical syndromes associated with CVB4 include aseptic meningitis (44%), respiratory symptoms (20%), encephalitis (14%), myocarditis and pericarditis (6%), and nonspecific febrile rash. Almost 100% of patients with CVB4 infections reported fever, 80% reported pharyngitis, and 25% reported rash. Rectal swabs are positive in 70% to 80% of patients regardless of symptoms, and the literature describes isolation of CVB4 in the epididymis.
Our patient's symptoms, particularly the mononucleosis-like syndrome with fever and rash not sparing palms and soles, as well as the reported risk factors, led to a long differential of infections, including primary HIV infection, early syphilis, infectious mononucleosis, and acute urethritis. Noninfectious causes such as DRESS syndrome or autoimmune diseases were also considered. Although ribavirin has been proven effective against CVB4, its use is only recommended for the treatment of acute myocarditis. Although coxsackievirus infections (both A and B) are responsible for about 20% to 25% of viral myocarditis, only 4% to 6% of patients with a CVB4 infection present with myocarditis. There are conflicting reports about blood-brain barrier penetration of ribavirin, hence the drug is not systematically recommended to treat neurologic complications of coxsackievirus infections. The recommended treatment for milder CVB4 cases is supportive care. Because of viral shedding in stool for up to 8 weeks, it's imperative to counsel patients about the fecal-oral transmission route and the importance of hand hygiene.
- Coxsackievirus infections, though common in children, may present in adults mimicking mononucleosis-like syndrome, but infections can also be severe, with neurologic and/or cardiac complications.
- Because coxsackievirus can be shed in stool for up to eight weeks, counseling is imperative to prevent viral spread.